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Mechanism of NMDA Receptor Inhibition and Activation.
Zhu S
,
Stein RA
,
Yoshioka C
,
Lee CH
,
Goehring A
,
Mchaourab HS
,
Gouaux E
.
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N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated, calcium-permeable ion channels that mediate synaptic transmission and underpin learning and memory. NMDAR dysfunction is directly implicated in diseases ranging from seizure to ischemia. Despite its fundamental importance, little is known about how the NMDAR transitions between inactive and active states and how small molecules inhibit or activate ion channel gating. Here, we report electron cryo-microscopy structures of the GluN1-GluN2B NMDA receptor in an ensemble of competitive antagonist-bound states, an agonist-bound form, and a state bound with agonists and the allosteric inhibitor Ro25-6981. Together with double electron-electron resonance experiments, we show how competitive antagonists rupture the ligand binding domain (LBD) gating "ring," how agonists retain the ring in a dimer-of-dimers configuration, and how allosteric inhibitors, acting within the amino terminal domain, further stabilize the LBD layer. These studies illuminate how the LBD gating ring is fundamental to signal transduction and gating in NMDARs.
Armstrong,
Measurement of conformational changes accompanying desensitization in an ionotropic glutamate receptor.
2006, Pubmed,
Xenbase
Armstrong,
Measurement of conformational changes accompanying desensitization in an ionotropic glutamate receptor.
2006,
Pubmed
,
Xenbase
Attwell,
Neuroenergetics and the kinetic design of excitatory synapses.
2005,
Pubmed
Baron,
[3H]5,7-dichlorokynurenic acid, a novel radioligand labels NMDA receptor-associated glycine binding sites.
1991,
Pubmed
Biasini,
SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information.
2014,
Pubmed
Chaudhry,
Stability of ligand-binding domain dimer assembly controls kainate receptor desensitization.
2009,
Pubmed
Cheng,
Single-Particle Cryo-EM at Crystallographic Resolution.
2015,
Pubmed
Cheriyan,
Heteromerization of ligand binding domains of N-methyl-D-aspartate receptor requires both coagonists, L-glutamate and glycine.
2015,
Pubmed
Dalmau,
Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.
2008,
Pubmed
Dzubay,
Kinetics of NMDA channel opening.
1996,
Pubmed
Dürr,
Structure and dynamics of AMPA receptor GluA2 in resting, pre-open, and desensitized states.
2014,
Pubmed
Endele,
Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.
2010,
Pubmed
Evans,
The effects of a series of omega-phosphonic alpha-carboxylic amino acids on electrically evoked and excitant amino acid-induced responses in isolated spinal cord preparations.
1982,
Pubmed
Fischer,
Ro 25-6981, a highly potent and selective blocker of N-methyl-D-aspartate receptors containing the NR2B subunit. Characterization in vitro.
1997,
Pubmed
,
Xenbase
Furukawa,
Mechanisms of activation, inhibition and specificity: crystal structures of the NMDA receptor NR1 ligand-binding core.
2003,
Pubmed
Furukawa,
Subunit arrangement and function in NMDA receptors.
2005,
Pubmed
Gielen,
Structural rearrangements of NR1/NR2A NMDA receptors during allosteric inhibition.
2008,
Pubmed
,
Xenbase
Gielen,
Mechanism of differential control of NMDA receptor activity by NR2 subunits.
2009,
Pubmed
Grant,
Measuring the optimal exposure for single particle cryo-EM using a 2.6 Å reconstruction of rotavirus VP6.
2015,
Pubmed
Jeschke,
Direct conversion of EPR dipolar time evolution data to distance distributions.
2002,
Pubmed
Jespersen,
Structural insights into competitive antagonism in NMDA receptors.
2014,
Pubmed
,
Xenbase
Johnson,
Glycine potentiates the NMDA response in cultured mouse brain neurons.
,
Pubmed
Karakas,
Structure of the zinc-bound amino-terminal domain of the NMDA receptor NR2B subunit.
2009,
Pubmed
,
Xenbase
Karakas,
Crystal structure of a heterotetrameric NMDA receptor ion channel.
2014,
Pubmed
Karakas,
Subunit arrangement and phenylethanolamine binding in GluN1/GluN2B NMDA receptors.
2011,
Pubmed
,
Xenbase
Kew,
A novel mechanism of activity-dependent NMDA receptor antagonism describes the effect of ifenprodil in rat cultured cortical neurones.
1996,
Pubmed
Lee,
NMDA receptor structures reveal subunit arrangement and pore architecture.
2014,
Pubmed
,
Xenbase
Lesca,
GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.
2013,
Pubmed
Mastronarde,
Automated electron microscope tomography using robust prediction of specimen movements.
2005,
Pubmed
Mayer,
Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones.
,
Pubmed
Mayer,
Emerging models of glutamate receptor ion channel structure and function.
2011,
Pubmed
,
Xenbase
McHaourab,
Toward the fourth dimension of membrane protein structure: insight into dynamics from spin-labeling EPR spectroscopy.
2011,
Pubmed
Meyerson,
Structural mechanism of glutamate receptor activation and desensitization.
2014,
Pubmed
Mindell,
Accurate determination of local defocus and specimen tilt in electron microscopy.
2003,
Pubmed
Mishra,
Conformational dynamics of the nucleotide binding domains and the power stroke of a heterodimeric ABC transporter.
2014,
Pubmed
Mony,
Molecular basis of positive allosteric modulation of GluN2B NMDA receptors by polyamines.
2011,
Pubmed
Monyer,
Heteromeric NMDA receptors: molecular and functional distinction of subtypes.
1992,
Pubmed
Moriyoshi,
Molecular cloning and characterization of the rat NMDA receptor.
1991,
Pubmed
,
Xenbase
Nowak,
Magnesium gates glutamate-activated channels in mouse central neurones.
,
Pubmed
Paoletti,
NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease.
2013,
Pubmed
Pettersen,
UCSF Chimera--a visualization system for exploratory research and analysis.
2004,
Pubmed
Schauder,
Glutamate receptor desensitization is mediated by changes in quaternary structure of the ligand binding domain.
2013,
Pubmed
Scheres,
RELION: implementation of a Bayesian approach to cryo-EM structure determination.
2012,
Pubmed
Scheres,
Prevention of overfitting in cryo-EM structure determination.
2012,
Pubmed
Sobolevsky,
X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor.
2009,
Pubmed
Stein,
A Straightforward Approach to the Analysis of Double Electron-Electron Resonance Data.
2015,
Pubmed
Suloway,
Automated molecular microscopy: the new Leginon system.
2005,
Pubmed
Sun,
Mechanism of glutamate receptor desensitization.
2002,
Pubmed
Traynelis,
Glutamate receptor ion channels: structure, regulation, and function.
2010,
Pubmed
Traynelis,
Control of proton sensitivity of the NMDA receptor by RNA splicing and polyamines.
1995,
Pubmed
,
Xenbase
Vergnano,
Zinc dynamics and action at excitatory synapses.
2014,
Pubmed
Vicini,
Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors.
1998,
Pubmed
Weston,
Conformational restriction blocks glutamate receptor desensitization.
2006,
Pubmed
Yuan,
Control of NMDA receptor function by the NR2 subunit amino-terminal domain.
2009,
Pubmed
,
Xenbase
Zheng,
Allosteric interaction between the amino terminal domain and the ligand binding domain of NR2A.
2001,
Pubmed
Zhu,
Genetically encoding a light switch in an ionotropic glutamate receptor reveals subunit-specific interfaces.
2014,
Pubmed
,
Xenbase
Zhu,
Allosteric signaling and dynamics of the clamshell-like NMDA receptor GluN1 N-terminal domain.
2013,
Pubmed
